MANIPAL INSTITUTE OF TECHNOLOGY
Cancer is one of the leading causes of death, with approximately 20 million new cases of cancer reported around the globe in 2020, accompanied by 10 million cancer deaths. Currently, the three most conventional treatments for cancer- chemotherapy, surgery, and radiation therapy, although effective, display side effects such as alopecia (hair loss), fatigue, and fertility-related problems. This has resulted in a search for a more effective method with lower side effects.
To prevent the growth of such cancers, the immune system searches and destroys abnormal cancer cells. Immune cells are often present inside and around the vicinity of the cancer mass. However, cancer cells possess mechanisms that hinder the functions of immune cells and prevent the destruction of the cancer cells. This is generally done by:
1. Down-regulation of synthesis of proteins which activate a response by immune cells, thus “hiding” from immune cells.
2. Exhibiting proteins on the surface of cancer cells that deactivate immune cell function.
3. Exhibiting genetic mutations, reducing the visibility of cancer cells to the immune system.
To overcome these challenges, multiple non-conventional immunotherapy methods have been devised, which fight cancers by bolstering the immune system. One such immunotherapeutic method is CAR (Chimeric Antigen Receptor) T Cell Therapy.
Mechanism of CAR T Cell Therapy
Cancer cells exhibit certain proteins known as tumor antigens – which produce a response from the immune system. T cells use their receptors to identify these antigens, and if the receptor detects an abnormal antigen – one only found in diseased cells, the T cell is turned “ON”, and it destroys the diseased cell. However, as mentioned before, cancer cells use certain mechanisms to inhibit their destruction. This helps the cancer cells to avoid detection and allow for their proliferation.
In CAR T Cell therapy, blood is extracted from a patient, and PBMCs (peripheral mononuclear blood cells – leucocytes and lymphocytes) are extracted from blood using a technique called leukapheresis. The T cells are then separated using centrifugation-based or standard cell separators. Cell surface marker-mediated techniques such as magnetic-activated cell sorting can be used to separate further classes of T cells. The isolated T cells are then genetically engineered to express a transgene that codes for a tumor-specific CAR. This gene transfer is carried out using retroviral or lentiviral vectors or viral transduction, and thus, these T cells now possess the receptors specific to cancer antigens. CAR T cells can also identify protein, carbohydrate, and glycolipid structures that are expressed on the tumor cell surface.
CARs – Chimeric Antigen Receptors have 3 primary domains:
1. Extracellular portion that contains antigen-recognition domain.
2. Transmembrane domain that anchors the Chimeric Antigen Receptors into the cell membrane.
3. Intracellular domain containing other domains which enhance T-cell proliferation and cytokine release.
A large quantity of these modified T-cells is then grown in the laboratory and then infused back into the patient. These cells bind to cancer-specific antigens, which turn the T cells “ON” and destroy the cancer cells.
Currently, there are some FDA-approved CAR T Cell therapies for blood cancers such as B-cell lymphomas, follicular lymphomas, and multiple myelomas. It has also been approved for acute lymphoblastic leukemias. CAR T Cell therapies also boast good remission rates. For now, however, these therapies are not used for solid tumors, as CAR T Cells might not be able to pass through the vascular endothelium.
Results from ZUMA-1 clinical trials, which used axicabtagene ciloleucel (trade name – Yescarta) showed good response with virtually no safety concerns in patients with recurring large B-cell lymphomas. 83% of patients responded to treatment and 58% exhibited complete responses. After a single Yescarta infusion, 47% of patients with refractory large B-cell lymphoma in the ZUMA-1 clinical survived. In certain trials, almost 90% of patients with B-cell acute lymphocytic leukemia, whose cancer had either relapsed or did not respond to conventional therapy, achieved long-lasting remission after undergoing CAR T-cell therapy.
The advantages of CAR T Cell therapy are:
1. Short treatment duration – Maximum of two weeks of hospitalization for one infusion of modified T cells.
2. Rapid recovery rates when used in conjunction with conventional treatment – 67% of childhood acute aggressive lymphoblastic leukemia patients were still in remission after six months. Remission rates as high as 94% have been recorded for aggressive blood cancers.
3. Longer remission periods than conventional treatment.
However, CAR T Cell therapy can also exhibit certain side effects such as:
3. Loss of appetite.
4. Cytokine Release Syndrome: This is caused due to immune cells responding to the new T cells and releasing a large number of cytokines into the bloodstream, leading to nausea, headaches, rash, low blood pressure, etc.
5. Though CAR T Cells are modified to recognize tumor antigens, they can sometimes mistakenly identify normal antigens and normal cells. Depending on the type of normal cells, side effects can be as bad as organ damage.
Despite these side effects, CAR T Cell therapy presents great promise and new advances are solidifying its position as a viable treatment option for cancer. Methods have been developed where the immune system can be stimulated without extracting the T cells. These are called “off-the-shelf” treatments (bispecific T-cell engaging antibodies) and have displayed great success rates in acute lymphoblastic leukemias. These proteins would be able to ignore healthy cells and selectively destroy only cancer cells. Thus, CAR T Cell could help in revolutionizing the field of cancer treatment and could help in saving countless lives.
About the Author
I am a 3rd year B Tech Biotechnology student at MIT Manipal. My plan post-graduation is to pursue a Masters in either genetics or cancer biology. I am currently working on eggshell waste and cancer stem cells review papers. I aim to familiarize myself with current cancer research.